1. Field of the Invention
The invention relates to a membrane module for substance-specific treatment of a fluid, comprising a housing, an inlet arrangement for feeding the fluid to be treated into a distribution space in the housing, an outlet arrangement for removing the treated fluid from the housing via a collection space, and first membrane elements arranged in the housing and having a porous, semipermeable wall, each having one end pointing toward the distribution space and the other toward the collection space and a cavity formed by the wall, wherein the first membrane elements are embedded in a first sealing compound at the end pointing toward the distribution space and in a second sealing compound at the end pointing toward the collection space, such that the ends extend through the sealing compounds and each of the cavities of the first membrane elements is open at the end pointing toward the distribution space as well as at the end pointing toward the collection space and opens into the distribution space and collection space.
The invention also relates to a process for substance-specific treatment of a fluid.
2. Discussion of Related Art
Substance-specific treatments of fluids are becoming increasingly important in such application areas such as biotechnology, medicine, and chemical technology. Fluids in the context of the present invention are understood to include gases, gas mixtures, and liquids in general, such as protein solutions, suspensions or clear solutions. An example of a substance-specific treatment is the isolation of active agents from cell suspensions in which genetically modified cells have produced substances such as antibodies, hormones, growth factors, or enzymes, usually in small concentrations. Other important applications are the extracorporeal removal of undesired substances from human blood plasma and extraction of components such as immunoglobulins or clotting factors from the plasma of donated blood. Finally, another broad application area is the catalytic or biocatalytic—enzymatic—treatment of liquids, such as the hydrolysis of oils by lipases immobilized in a matrix.
The substance-specific treatment of fluids is frequently conducted such that the fluid to be treated is brought into contact with a carrier material, on and/or in which functional groups or substances are immobilized that, in a specific, selective manner, interact with the target substance contained in the fluid, i.e., with the substance that is the object of the substance-specific treatment. Such interactions can be, for example, cation or anion exchange, hydrophilic/hydrophobic interaction, hydrogen bridge formation, affinity, or enzymatic or catalytic reactions, and the like. In affinity separation of substances, such as affinity chromatography, ligands are coupled to or immobilized in the carrier material. The ligands have the function of adsorptively binding a specific single target substance or an entire class of substances. This target substance is termed a ligate. Examples of class-specific ligands are positively charged diethylaminoethyl (DEAE) groups or negatively charged sulfonic acid (SO3) groups, which adsorb the class of positively or negatively charged molecules, respectively. Specific ligands are, for example, antibodies against a certain protein, which is bound as a ligate to the antibody.
Substance-specific treatments in the context of the present invention, however, are also understood to be those treatments by which molecules or particles are separated or retained due to their size. For a number of applications, it is desirable or necessary to subject a fluid to be treated to several, possibly different, substance-specific treatments. Thus, in the case of filtration processes of suspensions with differing particle fractions, it may be necessary to first prefilter larger particles with a coarse, open-pored prefilter and then to subject the filtrate to further substance-specific treatment, according to size or to affinity for a ligand, for example.
The primary criteria in the substance-specific treatment of fluids are productivity and selectivity. With a view toward productivity, it is important that, per unit of volume, as many functional groups as possible are available that can interact with the target substance contained in the fluid to be treated. At the same time, it is desirable to maximize the transport of the target substance to the functional groups or substances. In many such processes for substance-specific treatment of fluids, membranes with a porous structure are now used as carrier materials for functional groups. Due to their porous structure, membranes present a large inner surface area so that a large number of functional groups can be coupled to the membranes at a high concentration per unit volume. These functional groups interact with the fluids to be treated that pass through the membrane. (See, for example, E. Klein, “Affinity Membranes”, John Wiley & Sons, Inc., 1991; S. Brandt et al., “Membrane-Based Affinity Technology for Commercial Scale Purifications,” Bio/Technology Vol. 6 (1988), 779-782.)
Adaptation to the requirements of the treatment method can be attained via the type of the membrane used. Membranes are available in the form of hollow fibers or as flat membranes made from a wide variety of materials so that adaptation to the physicochemical properties of the fluids to be treated is possible. In addition, the pore size of the membranes can be adjusted such that a fluid to be treated, for example, containing a target substance, can pass through the membrane convectively, and, in the case of binding of the target substance to the interacting groups, there is no blockage of the membrane.
For a given linear flow rate, the thickness of the membrane wall can influence the residence time of the fluid to be treated in the membrane and the pressure drop during flow. Due to their generally thin walls (<300 μm, for example), membranes are distinguished by short transport distances for the fluid to be treated to interacting groups immobilized in the membranes, for example, resulting in relatively short residence times, low pressure drops, high linear flow rates, and therefore, high binding rates.
A number of devices containing such membranes have been described that are used in processes for substance-specific treatment of fluids. A distinction must be made here between the so-called dead-end mode or dead-end modules and cross-flow mode or cross-flow modules.
In cross-flow mode, the fluid to be treated flows as a feed stream parallel to one side of the membrane and a portion of the feed stream flows through the membrane as the permeate. It follows that in cross-flow modules only a part of the liquid to be treated, i.e., the part that passes through the membrane wall as a permeate, can undergo substance-specific treatment, which generally occurs in the membrane wall or possibly in the outer space of the membranes.
In dead-end mode, on the other hand, the entire fluid entering the membrane module as a feed stream is directed through the membrane and is removed as a filtrate or permeate from the downstream side of the membrane, which is opposite the inlet side.
WO 90/05018 discloses a cross-flow module with hollow-fiber membranes for use in affinity separation processes. In this module, a ligate-containing liquid is directed into the module housing via an inlet arrangement and flows tangentially over one side of the hollow-fiber membranes in and to which the ligands have been coupled. A portion of the liquid enters the membrane and flows through it, the ligates becoming attached to the ligands, and exits as a permeate stream on the side of the membrane opposite the inlet side. The retentate and permeate streams are removed via separate outlet arrangements.
In EP-A-0 341 413, an adsorber module is described for treatment of whole blood in which the hollow-fiber membranes, which are contained in the module embedded in sealing compounds at both ends and provided with ligands, are subjected to blood flow through the lumen in cross-flow mode. Plasma enters the outer space enclosing the hollow-fiber membranes as a permeate through the hollow-fiber membrane wall, the treatment of the plasma taking place in the membrane wall. In a specific embodiment, this module has no outlet for the permeate. Instead, the plasma separated as a permeate accumulates in the outer space surrounding the capillaries, and due to the developing pressure conditions, re-enters the lumen of the hollow-fiber membrane through the hollow-fiber membrane wall. In this module concept the permeate stream must pass through the membrane wall twice so that the flow through the membrane is almost zero over a large area. On the other hand, the flow is very high in the inlet region. A module of this type has the disadvantage that, in regions of high flow, the binding capacity is soon exhausted while the capacity in regions of low flow is not fully exploited.
DE-A-33 02 384 describes a dead-end module for blood plasma treatment containing hollow-fiber membranes. This module contains two adjacent hollow-fiber-membrane bundles, connected in series, for separation of pathological molecules from blood plasma by fractionation according to particle size. The ends of the hollow-fiber membranes of the two membrane bundles are embedded together in the module housing such that the hollow-fiber membranes of the first membrane bundle are open at the end toward the module inlet and closed at the other end, while the hollow-fiber membranes of the second membrane bundle are open at the end toward the module outlet and closed at the other end. The open ends of the two hollow-fiber bundles are therefore arranged oppositely. During operation, the blood plasma to be treated and from which the pathogenic components are to be filtered off, flows in dead-end mode initially via the open ends of the hollow-fiber membranes of the first membrane bundle into the lumen of these membranes and through their walls into the extraluminal region. Once filtered in this manner, the plasma then flows from the outside to the inside into the lumen of the hollow-fiber membranes of the second membrane bundle and leaves them through their open ends.
DE-A-37 09 432 discloses a dead-end module for sterilization of liquid media. This module contains two adjacent hollow-fiber-membrane bundles connected in series and is structurally similar to that described in DE-A-33 02 384. In the module of DE-A-37 09 432, the membrane of at least one of the hollow-fiber bundles can carry adsorptive material. In addition, the bundles may be surrounded by an additional filtration device that is in the form of a flexible, semipermeable tube and can also carry adsorptive material.
U.S. Pat. No. 5,693,230 also discloses a dead-end module with two groups of hollow-fiber membranes, wherein all the hollow-fiber membranes are open at one end and closed at the other. In this case, the module contains first hollow-fiber membranes for feeding in the fluid to be treated and second hollow-fiber membranes to remove the treated fluid. The fluid to be treated enters through the open ends of the first hollow-fiber membranes into their lumina, passes through the porous wall of these membranes into the outer space surrounding the first and second hollow-fiber membranes, and is directed from there through the porous wall of the second hollow-fiber membranes into their lumina and discharged through their open ends. In the outer space, the fluid is brought into contact with a treatment medium present there, and is treated.
In contrast to cross-flow modules, dead-end modules generally have the disadvantage that their applicability in the treatment of suspensions is very severely restricted, because in this design, the suspended particles are, as a rule, retained by the membrane used. Moreover, prior art dead-end membrane modules are less versatile in the sense that only a single substance-specific treatment can generally be carried out on a fluid to be treated.
It is therefore an object of the present invention to provide a membrane module of the type initially described in which the disadvantages of prior art membrane modules are reduced to at least some extent, and which is suitable for substance-specific treatment of both clear solutions and, in particular, suspensions, and can be flexibly adapted for the particular fluid treatment required, and, in particular, allows various types of substance-specific treatments to be carried out in direct succession.
It is furthermore an object of the present invention to provide a process for efficient substance-specific treatment of fluids using a module comprising semipermeable membranes of porous structure, which at least reduces the aforementioned disadvantages and allows, for example, improved utilization of the functional groups immobilized in the module and the substance-specific treatment of suspensions.